OXPHOS - a metabolic switch driven by tumor microenvironment and resistance to therapy in prostate carcinoma

Tumor cells exhibit metabolic reprogramming according to microenvironmental scenarios (i.e. stroma composition and/or anticancer drugs burden) to meet their demands for energy, rapid proliferation, metastasis and progression. In our experimental model, a vicious metabolic synergy between CAFs and prostate cancer (PCa) cells has been described as a pivotal engine allowing cancer cells to achieve aggressive features and evolve their malignancy. Such metabolic crosstalk is mainly based on the OXPHOS rewiring of PCa cells induced by highly glycolytic CAFs through the establishment of tumor:stroma lactate shuttle. In the first part of this study, we highlighted a peculiar CAFs conditioning of PCa cells in terms of OXPHOS upgrading and enhancement. Indeed, we observed that CAFs induce a SIRT1/PGC-1α axis activation in PCa cells, leading to the accumulation of mitochondrial ROS and TCA cycle oncometabolites (succinate/fumarate) that are both closely related to EMT engagement and PCa invasiveness. Indeed, we found that CAFs-exacerbated mitochondrial ROS are crucial for the oxidation of critical targets (Src, PKM2) needed for the metabolic reprogramming toward OXPHOS established in CAFs-exposed PCa cells. On the other hand, succinate is able to maintain CAFs-induced HIF-1α activation and the HIF-1- dependent malignant phenotype of PCa cells. Furthermore, we intriguingly observed a mechanism of mitochondrial transfer elicited by CAFs in order to further boost OXPHOS exploitation, mitochondrial ROS generation and invasiveness of PCa cells. Among microenvironmental cues, chemotherapy resistance has been increasingly and finely associated to the metabolic reprogramming of resistant cancer cells. In the second part of this study, we metabolically characterized docetaxel-resistant PCa cells and we clearly outlined a metabolic adaptation of resistant cancer cells compared to the sensitive counterpart. Docetaxel-resistant PCa cells undergo a Warburg escape towards OXPHOS addiction in order to ensure metabolic advantages during acquisition of resistant phenotype. Together with lactate and glucose, we also found an higher glutamine mitochondrial exploitation by docetaxel-resistant cells. Furthermore, we appreciated a role of CAFs in modulating the response to drug exposure by protecting sensitive and resistant PCa cells. We found that such metabolic/resistant phenotype can be counteracted either by metformin (or other mitocans) treatment or by overexpressing miR-205, a downregulated miRNA orchestrating prostate tumor:stroma crosstalk. Taken together, all the data obtained in our study highlight the role of OXPHOS as an important shared metabolic state between chemotherapy resistance and symbiosis with microenvironment PCa cells.